<p>(A) Representative IHC staining images showing the expressions of SLAMF7 and CCL2 in HCC samples. Scale bar: 200 μm (left) and 20 μm (right). (B) The prognostic prediction performances of SLAMF7 in combination with CCL2 for OS and DFS in our Fudan LCI HCC cohort.</p>
<p>(A) Immunoblot assays showing the phosphorylated or non-phosphorylated ERK1/2, p38, and JNK proteins in the indicated HCC cells. (B) Flow cytometry analyses of CD80 and CD206 expressions in THP-1-differentiated macrophages cocultured with the indicated HCC cells. (C) Chemotaxis assays showing the effect of supernatants from the indicated coculture systems on the migration abilities of THP-1-differentiated macrophages. Scale bar: 100 μm. (D) qPCR and ELISA analyses of CCL2 transcriptional and secretory levels in the indicated HCC cells. (E) Immunoblot assays of phosphorylated or non-phosphorylated ERK1/2, p38, and JNK proteins in the indicated HCC cells. (F) ChIP-qPCR analyses of ATF2 binding to the CCL2 gene promoter in HCC cell lines with SLAMF7 overexpression and knockdown. (G) Immunoblot assays of SLAMF7, and ATF2 protein levels in the indicated HCC cells. **P<0.01, and ***P<0.001, Student’s t test. Experiments were repeated three time and results were present as the mean ± SD.</p>
Abstract Induction of cell death and inhibition of cell survival are the main principles of cancer therapy. Resistance to chemotherapeutic agents is a major problem in oncology, which limits the effectiveness of anticancer drugs. A variety of factors contribute to drug resistance, including host factors, specific genetic or epigenetic alterations in the cancer cells and so on. Although various mechanisms by which cancer cells become resistant to anticancer drugs in the microenvironment have been well elucidated, how to circumvent this resistance to improve anticancer efficacy remains to be defined. Autophagy, an important homeostatic cellular recycling mechanism, is now emerging as a crucial player in response to metabolic and therapeutic stresses, which attempts to maintain/restore metabolic homeostasis through the catabolic lysis of excessive or unnecessary proteins and injured or aged organelles. Recently, several studies have shown that autophagy constitutes a potential target for cancer therapy and the induction of autophagy in response to therapeutics can be viewed as having a prodeath or a prosurvival role, which contributes to the anticancer efficacy of these drugs as well as drug resistance. Thus, understanding the novel function of autophagy may allow us to develop a promising therapeutic strategy to enhance the effects of chemotherapy and improve clinical outcomes in the treatment of cancer patients.
<div>Abstract<p>Immune checkpoint inhibitors have limited efficacy in hepatocellular carcinoma (HCC). Macrophages are the most abundant immune cells in HCC, suggesting that a better understanding of the intrinsic processes by which tumor cells regulate macrophages could help identify strategies to improve response to immunotherapy. As signaling lymphocytic activation molecule (SLAM) family members regulate various immune functions, we investigated the role of specific SLAM receptors in the immunobiology of HCC. Comparison of the transcriptomic landscapes of immunotherapy-responsive and nonresponsive patients with advanced HCC identified SLAMF7 upregulation in immunotherapy-responsive HCC, and patients with HCC who responded to immunotherapy also displayed higher serum levels of SLAMF7. Loss of Slamf7 in liver-specific knockout mice led to increased hepatocarcinogenesis and metastasis, elevated immunosuppressive macrophage infiltration, and upregulated PD-1 expression in CD8<sup>+</sup> T cells. HCC cell-intrinsic SLAMF7 suppressed MAPK/ATF2-mediated CCL2 expression to regulate macrophage migration and polarization <i>in vitro</i>. Mechanistically, SLAMF7 associated with SH2 domain-containing adaptor protein B (SHB) through its cytoplasmic 304 tyrosine site to facilitate the recruitment of SHIP1 to SLAMF7 and inhibit the ubiquitination of TRAF6, thereby attenuating MAPK pathway activation and <i>CCL2</i> transcription. Pharmacological antagonism of the CCL2/CCR2 axis potentiated the therapeutic effect of anti–PD-1 antibody in orthotopic HCC mouse models with low SLAMF7 expression. In conclusion, this study highlights SLAMF7 as a regulator of macrophage function and a potential predictive biomarker of immunotherapy response in HCC. Strategies targeting CCL2 signaling to induce macrophage repolarization in HCC with low SLAMF7 might enhance the efficacy of immunotherapy.</p>Significance:<p>CCL2 upregulation caused by SLAMF7 deficiency in hepatocellular carcinoma cells induces immunosuppressive macrophage polarization and confers resistance to immune checkpoint blockade, providing potential biomarkers and targets to improve immunotherapy response in patients.</p></div>
<p>(A) Top: Schematic showing the administration schedule of clophosome in the indicated orthotopic HCC mouse models. Bottom: Gross appearance of the liver bearing Hepa1-6 tumors in the indicated treatment groups. (B) The tumor weight and tumor volume of each group at the study endpoint (5 mice per group). NS, not significant, **P<0.01, and ***P<0.001, one-way ANOVA with a post hoc LSD test.</p>
<p>(A) The liver and kidney functions of C57BL/6 mice with orthotopic Hepa1-6 tumors receiving RS102895 and anti-PD-1 antibody monotherapy or combination therapy at the study endpoint. (B) Gross appearance of the liver bearing Hepa1-6-shSlamf7 tumors in the indicated treatment groups. (C) The tumor weight and tumor volume of each group at the study endpoint (5 mice per group). (D) Gross appearance of the liver bearing Hepa1-6-Slamf7 tumors in the indicated treatment groups. (E) The tumor weight and tumor volume of each group at the study endpoint (5 mice per group). (F) Schematic showing the schedule of elotuzumab treatment in mice bearing MM and HCC subcutaneous tumors. (G) Gross appearance of the subcutaneous tumors from the indicated groups. (H) The tumor weight of each group at the endpoint. (I) Volumes of subcutaneous tumors in each group during treatment. NS, not significant, ***P<0.001, one-way ANOVA with a post hoc LSD test (or Student’s t test in part H and I).</p>
<p>(A) Representative IHC staining images showing the expressions of SLAMF7, p-STAT1, and p-STAT3 in HCC samples from Fudan LCI cohort. Scale bar: 200 μm (left) and 20 μm (right). (B) Representative immunofluorescence staining (left) and the infiltration levels (right) of exhausted T cells (CD8+ PD-1+ TCF1-) in HCC tumors with high and low SLAMF7 protein expression in the Fudan LCI cohort. Scale bar: 20μm. *P<0.05, Student’s t test.</p>
<p>(A) Top: Schematic showing the administration schedule of clophosome in the indicated orthotopic HCC mouse models. Bottom: Gross appearance of the liver bearing Hepa1-6 tumors in the indicated treatment groups. (B) The tumor weight and tumor volume of each group at the study endpoint (5 mice per group). NS, not significant, **P<0.01, and ***P<0.001, one-way ANOVA with a post hoc LSD test.</p>
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